Systems and methods for increasing convective clearance of undesired particles in a microfluidic device

ABSTRACT

A microfluidic device for increasing convective clearance of particles from a fluid is provided. In some implementations, described herein the microfluidic device includes multiple layers that each define infusate, blood, and filtrate channels. Each of the channels have a pressure profile. The device can also include one or more pressure control features. The pressure control feature controls a difference between the pressure profiles along a length of the device. For example, the pressure control feature can control the difference between the pressure profile of the filtrate channel and the pressure profile of the blood channel. In some implementations, the pressure control feature controls the pressure difference between two channels such that the difference varies along the length of the channels by less than 50% of the pressure difference between the channels at the channels&#39; inlets.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation in part of U.S. patent applicationSer. No. 14/832,875 filed Aug. 21, 2015 and titled “SYSTEMS AND METHODSFOR INCREASING CONVECTIVE CLEARANCE OF UNDESIRED PARTICLES IN AMICROFLUIDIC DEVICE,” which claims priority to and benefit of U.S.Provisional Patent Application No. 62/040,131 filed on Aug. 21, 2014 andtitled “SYSTEMS AND METHODS FOR INCREASING CONVECTIVE CLEARANCE OFUNDESIRED PARTICLES IN A MICROFLUIDIC DEVICE,” each of which are hereinincorporated by reference in their entirety. U.S. patent applicationSer. No. 14/832,875 is also a continuation in part of U.S. patentapplication Ser. No. 13/739,701 filed on Jan. 11, 2013 and titled“SYSTEMS AND METHODS FOR INCREASING CONVECTIVE CLEARANCE OF UNDESIREDPARTICLES IN A MICROFLUIDIC DEVICE,” and a continuation in part of U.S.patent application Ser. No. 13/739,685 filed on Jan. 11, 2013 and titled“SYSTEMS AND METHODS FOR INCREASING CONVECTIVE CLEARANCE OF UNDESIREDPARTICLES IN A MICROFLUIDIC DEVICE,” each of which are hereinincorporated by reference in their entirety.

BACKGROUND

A dialysis device contains a series of fluid channels separated by apermeable membrane. Convective clearance of solutes from blood in thedevice is determined by the transmembrane pressure in the device.Typically, the fluid in adjacent channels flows in opposite directionsand the channels have a non-linear fluid to red-blood cell volumeprofile along their lengths. Increasing the convective clearancerequires decreasing the fluid to red-blood cell volume in the channelcarrying blood, which can result in an unsafe hematocrit level in thechannel. Therefore, it is desirable to increase the amount of convectiveclearance within a compact dialysis device while maintaining safehematocrit levels throughout the blood channel.

SUMMARY OF THE DISCLOSURE

According to one aspect of the disclosure, a microfluidic deviceincludes a first layer that defines an infusate channel. The infusatechannel has a first pressure profile. The device also includes a secondlayer that defines a blood channel complementary to and in fluidiccommunication with the infusate channel. The blood channel has a secondpressure profile. The device also includes a third layer defining afiltrate channel that is complementary to and in fluidic communicationwith the blood channel. The filtrate channel has a third pressureprofile. The device also includes a first interchannel flow barrier thatseparates the infusate channel and the blood channel. The deviceincludes a second interchannel flow barrier that separates the filtratechannel and the blood channel. The device includes a first controllableflow control device that is configured to actively control a slope ofthe third pressure profile along a length of the filtrate channelrelative to the slope of the second pressure profile along the length ofthe blood channel. The device includes a control system that isconfigured to modify a state of the first controllable flow controldevice.

In some implementations, the control system is configured to achieve anoperational state where the slope of the third pressure profile isgreater than the slope of the second pressure profile. In otherimplementations, the control system is configured to achieve anoperational state where the slope of the third pressure profile is lessthan the slope of the second pressure profile. In other implementations,the control system is configured to achieve an operational state wherethe slope of the third pressure profile is substantially parallel to theslope of the second pressure profile.

In some implementations, the first controllable flow control device isconfigured such that a pressure difference along a length of the bloodchannel and the filtrate channel does not vary by more than 50% of anaverage pressure difference between the blood channel and the filtratechannel. In some implementations, the control system is configured tocontrol the first controllable flow control device to maintain apressure difference between a pressure of a first fluid flowing throughthe blood channel and a pressure of a second fluid flowing through thefiltrate channel that is below a critical transmembrane pressure.

In some implementations, the device includes at least one pressuresensor, and the control system is configured to modify the state of thefirst controllable flow control device responsive to an output of the atleast one pressure sensor. In some implementations, the firstcontrollable flow control device is one of a recirculating pump, aproportional valve, a diaphragm chamber, and an outflow pump.

In some implementations, the device includes at least two controllableflow control devices configured to actively control the slope of thethird pressure profile along the length of the filtrate channel relativeto the slope of the second pressure profile along the length of theblood channel. In some implementations, the second controllable flowcontrol device is configured to actively control the slope of the firstpressure profile along a length of the infusate channel. The secondcontrollable flow control device can be one of a recirculating pump, aproportional valve, a diaphragm chamber, and an influx pump.

In some implementations, the blood channel has a height in the range ofabout 50 μm to about 500 μm, a width in the range of about 50 μm toabout 900 μm, and a length in the range of about 3 cm to about 30 cm. Insome implementations, the first interchannel flow barrier is a sterilitybarrier.

According to another aspect of the disclosure, a microfluidic deviceincludes a first layer defining a blood channel. The blood channelincludes an inlet and an outlet and has a first pressure profile. Thedevice also includes a second layer defining a filtrate channel that iscomplementary to and in fluidic communication with the filtrate channel.The filtrate channel has a second pressure profile. The device alsoincludes a first interchannel flow barrier separating the blood channeland the filtrate channel. The first interchannel flow barrier allows aportion of a fluid flowing into the inlet of the blood channel to flowthrough the first interchannel flow barrier and into the filtratechannel. The device also includes a first controllable flow controldevice to control a difference between the first pressure profile andthe second pressure profile along a length of the blood channel. Thedevice also includes a control system that is configured to modify astate of the first controllable flow control device to set thedifference between the first pressure profile and the second pressureprofile.

In some implementations, setting the difference between the firstpressure profile and the second pressure profile includes modifying thestate of the first controllable flow control device such that thedifference is greater than or less than a critical transmembranepressure. In some implementations, setting the difference between thefirst pressure profile and the second pressure profile includesmodifying the state of the first controllable flow control device suchthat the difference is greater toward the outlet of the blood channelthan toward the inlet of the blood channel.

In some implementations, the blood channel has a height in a range ofabout 50 μm to about 500 μm, a width in the range of about 50 μm toabout 900 μm, and a length in the range of about 3 cm to about 30 cm.

In some implementations, the device includes a second controllable flowcontrol device to control the difference between the first pressureprofile and the second pressure profile along the length of the bloodchannel. In some implementations, the first and second controllable flowcontrol devices are one of a recirculating pump, a proportional valve, adiaphragm chamber, and an outflow pump. The device can also include atleast one sensor in the filtrate channel and the blood channel.

According to another aspect of the disclosure, a method includesintroducing a first fluid into a first inlet of an infusate channeldefined in a first layer and having a first pressure profile. The methodalso includes introducing blood into a second inlet of a blood channelthat is complementary to and in fluidic communication with the infusatechannel. The blood channel has a second pressure profile and is definedin a second layer. The method also includes introducing a second fluidinto a third inlet of a filtrate channel that is complementary to and influidic communication with the blood channel. The blood channel isdefined in a third layer and has a third pressure profile. The methodalso includes setting, by a control system with a first controllableflow control device, a first slope of the third pressure profile along alength of the filtrate channel relative to the slope of the secondpressure profile along the length of the blood channel. The method alsoincludes setting, by the control system with the first controllable flowcontrol device, a second slope of the third pressure profile along thelength of the filtrate channel relative to the slope of the secondpressure profile along the length of the blood channel.

In some implementations, setting the second slope of the third pressureprofile includes modifying, by the control system, a state of the firstcontrollable flow control device such that the second slope of the thirdpressure profile is greater than the slope of the second pressureprofile. In some implementations, setting the second slope of the thirdpressure profile includes modifying, by the control system, the state ofthe first controllable flow control device such that the second slope ofthe third pressure profile is less than the slope of the second pressureprofile. In some implementations, setting the second slope of the thirdpressure profile includes modifying, by the control system, the state ofthe first controllable flow control device such that the slope of thethird pressure profile is substantially parallel to the slope of thesecond pressure profile. In some implementations, the method includesmodifying, by the control system, a state of the first controllable flowcontrol device to maintain a pressure difference between a pressure ofthe blood and a pressure of the second fluid is below a criticaltransmembrane pressure.

In some implementations, the method includes modifying, by the controlsystem, the state of the first controllable flow control device tomaintain a pressure difference along a length of the blood channel andthe filtrate channel that does not vary by more than 50% of an averagepressure difference between the blood channel and the filtrate channel.

In some implementations, the method includes setting, by the controlsystem with a second controllable flow control device, the first slopeof the third pressure profile along the length of the filtrate channelrelative to the slope of the second pressure profile along the length ofthe blood channel. The method also includes setting, by the controlsystem with the second controllable flow control device, the secondslope of the third pressure profile.

In some implementations, the method includes receiving, by the controlsystem from at least one pressure sensor, at least one pressure reading.The second slope of the third pressure profile is then set responsive tothe at least one pressure reading. In some implementations, the firstcontrollable flow control device is one of a recirculating pump, aproportional valve, a diaphragm chamber, and an outflow pump.

In some implementations, the blood channel has a height in a range ofabout 50 μm to about 500 μm, a width in the range of about 50 μm toabout 900 μm, and a length in the range of about 3 cm to about 30 cm.

According to another aspect of the disclosure, a method includesintroducing blood into a first inlet of a blood channel. The blood has afirst pressure profile. The method also includes introducing a fluidinto a second inlet of a filtrate channel that is complementary to andin fluidic communication with the blood channel. The fluid has a secondpressure profile. The method also includes controlling, by a controlsystem, a state of a first controllable flow control device to set afirst difference between the second pressure profile along a length ofthe filtrate channel and the first pressure profile along a length ofthe blood channel. The method also includes modifying, by a controlsystem, the state of the first controllable flow control device to set asecond difference between the second pressure profile along the lengthof the filtrate channel and the first pressure profile along the lengthof the blood channel.

In some implementations, the second difference is less than a criticaltransmembrane pressure. In some implementations, the blood channel has aheight in a range of about 50 μm to about 500 μm, a width in the rangeof about 50 μm to about 900 μm, and a length in the range of about 3 cmto about 30 cm.

The method can also include controlling, by the control system, a stateof a second controllable flow control device to set the first differencebetween the second pressure profile along the length of the filtratechannel and the first pressure profile along the length of the bloodchannel. The method can also include modifying, by the control system,the state of the second controllable flow control device to set thesecond difference between the second pressure profile along the lengthof the filtrate channel and the first pressure profile along a length ofthe blood channel.

In some implementations, the first controllable flow control device isone of a recirculating pump, a proportional valve, a diaphragm chamber,and an outflow pump. The method can also include receiving, by thecontrol system from at least one pressure sensor, at least one pressurereading, and then setting a state of the first controllable flow controldevice responsive to the received at least one pressure reading.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings are not intended to be drawn to scale. Likereference numbers and designations in the various drawings indicate likeelements. For purposes of clarity, not every component may be labeled inevery drawing.

FIG. 1A illustrates a perspective view of an example microfluidicconvective clearance device.

FIG. 1B illustrates an example blood substrate layer suitable for use inthe microfluidic convective clearance device of FIG. 1A.

FIG. 1C illustrates a cross-sectional view of a first microfluidicconvective clearance device layer for use in hemofiltration deviceillustrated in FIG. 1A.

FIG. 1D illustrates a cross-sectional view of a second microfluidicconvective clearance device layer for use in hemofiltration deviceillustrated in FIG. 1A.

FIG. 1E illustrates a cross-sectional view of a third microfluidicconvective clearance device layer for use in hemofiltration deviceillustrated in FIG. 1A.

FIGS. 2A-2H depict the device of FIG. 1C at various points in themanufacturing process, according to an illustrative implementation.

FIG. 3 illustrates an example block diagram of a control system that canbe used with the devices of FIG. 1A, according to an illustrativeimplementation.

FIG. 4 illustrates a flow diagram of a method for filtering liquidcontaining an analyte, according to an illustrative implementation.

FIGS. 5A and 5B illustrate cross-sectional views of a microfluidicconvective clearance device for use in hemofiltration.

FIGS. 5C-5G illustrate graphs of example pressure profiles of each ofthe channels of microfluidic convective clearance device, such as thatillustrated in FIGS. 5A and 5B.

FIGS. 6A-6D illustrate cross-sectional views of example microfluidicconvective clearance devices that include elements to compensate forpressure drop along the length of the device.

FIG. 7 illustrates a cross-sectional view of a microfluidic convectiveclearance device with membrane support features.

FIG. 8A illustrates a cross-sectional view along a length of amicrofluidic convective clearance device with controlled infusion areas.

FIGS. 8B and 8C illustrate a cross-sectional view across a width of themicrofluidic convective clearance device illustrated in FIG. 8A.

FIG. 9 illustrates a cross-sectional view of a microfluidic convectiveclearance device with infusion and filtration zones.

FIG. 10 illustrates a cross-sectional view of a microfluidic convectiveclearance device with individual chambers within the membranes.

FIG. 11 illustrates a flow chart of an example method for cleansing afluid using a microfluidic convective clearance device.

FIG. 12 illustrates a graph comparing example transmembrane pressures tothe flux across a filtrate membrane in a microfluidic convectiveclearance device, such as that illustrated in FIGS. 5A and 5B.

FIG. 13 illustrates a cross-sectional view of an example two-layermicrofluidic convective clearance device for use in hemofiltration.

FIG. 14 illustrates a flow chart of an example method for cleansing afluid using a microfluidic convective clearance device.

DETAILED DESCRIPTION

Following below are more detailed descriptions of various conceptsrelated to, and implementations of, a device for increasing convectivetransport of solutes in blood within a dialysis system. The variousconcepts introduced above and discussed in greater detail below may beimplemented in any of numerous ways, as the described concepts are notlimited to any particular manner of implementation. Examples of specificimplementations and applications are provided primarily for illustrativepurposes.

FIG. 1A is a depiction of a microfluidic convective clearance device100. The device 100 is composed of eight layers 102. In someimplementations, each layer 102 includes 96 channels, with each channelconfigured to provide convective therapy. In some implementations, themicrofluidic convective clearance device 100, by varying the number ofchannels per layer or the number of layers, can include between 80 and7000 channels to match the size of the patient, the duration of therapy,and the desired clearance dosage. Each layer 102 includes a infusatesubstrate, a blood flow substrate, and a filtrate substrate. Thechannels within each substrate are separated from the channels indifferent substrates by permeable membranes (also referred to asinterchannel flow barriers). In other implementations, channels of afirst substrate are separated from channels of a second substrate by awall of one of the substrates (another form of interchannel flowbarrier), with fluid flowing between the channels through apertures thatpass through the wall separating the channels. The microfluidicconvective clearance device 100 also includes a blood inlet manifold 110and a blood outlet manifold 112, both coupled to the blood channels forthe introduction and removal of blood from the device 100. A filtrateinlet manifold 114 and a filtrate outlet manifold 116 are coupled to thefiltrate channels for the introduction and removal of filtrate from thedevice 100. The microfluidic convective clearance device 100 alsoincludes an infusate inlet manifold 111 and an infusate outlet manifold113 for the introduction and removal of infusate from the device. Insome implementations, the channels within the blood inlet and outletmanifolds are arranged in a trunk and branch configuration. In a trunkand branch configuration a primary trunk branches multiples times intosmaller branches. In some implementations, the branching in themanifolds mimics characteristics of branching in the vasculature of thebody, for example, following Murray's law and including relativelysmooth transitions between channels to protect blood health.

Example configurations for the layer 102 of the device 100 are describedbelow in relation to FIGS. 1C-1E. As an overview, each layer 102 isparallel to each other layer 102. Each substrate in a layer has athickness in the range of about 10 microns to about 10 millimeters, andthe membrane 108 has thickness in the range of about 500 nanometers toabout 1 millimeter. In some implementations, adjacent layers 102 can bein contact with one another. In other implementations, the layers 102can be separated by a distance of about 500 microns or more, asillustrated in FIG. 1A.

The substrates of each layer can be made of a thermoplastic, such aspolystyrene, polycarbonate, polyimide, or cyclic olefin copolymer (COC),biodegradable polyesters, such as polycaprolactone (PCL), or softelastomers such as polyglycerol sebacate (PGS). The substrate layers mayalternatively be made of polydimethylsiloxane (PDMS),poly(N-isopropylacrylamide), or nanotubes or nanowires formed from, forexample, carbon or zinc oxide. In some implementations, the substratesare made of an insulating material to maintain temperature stability. Insome implementations, the channels can be coated with cytophilic orcytophobic materials to promote or prevent the growth of cells, such asvascular endothelial cells, in the channels. The channels in the bloodsubstrate layer 104 may also be coated with an anticoagulant to helpprevent clotting of the blood in the blood substrate layer 104.

FIG. 1B illustrates an example blood substrate layer 104 suitable foruse in the microfluidic convective clearance device of FIG. 1A. Theblood substrate layer 104 allows blood to be distributed across arelatively large surface area within the device 100. The network ofchannels includes multiple blood channels 126. Blood is supplied andremoved from the blood channels through biomimetic branching structures119. Each branching structure 119 includes a primary channel 118, aplurality of secondary channels 120, and a plurality of tertiarychannels 122. In some implementations, the blood channels 126 have aheight in the range of about 50 μm to about 500 μm, a width in the rangeof about 50 μm to about 900 μm, and a length in the range of about 3 cmto about 30 cm or about 15 cm to about 25 cm.

FIG. 1C is a cross-sectional view of a first microfluidic convectiveclearance device layer 100 a for use in hemofiltration system such asthat illustrated in FIG. 1A. The convective clearance device layer 100 aincludes a blood channel 102 a, an infusate channel 104 a, and a wastechannel 106 a (also referred to as a “filtrate channel”). A firstmembrane 108 a separates the blood channel 102 a from the infusatechannel 104 a, and a second membrane 110 a separates the blood channel102 a from the waste channel 106 a. The infusate channel 104 a and thewaste channel 106 a also include structural supports 112 a.

The blood channel 102 a has a depth in the range of about 50 microns toabout 500 microns, a width in the range of about 50 microns to about 900microns, and a length in the range of about 3 centimeters to about 20centimeters. The infusate channel 104 a is defined by an infusatesubstrate 114 a and the waste channel 106 a is defined by a wastesubstrate 116 a (also referred to as a “filtrate substrate”). Thesubstrates 114 a and 116 a can be made from a polystyrene,polycarbonate, polyimide, polysulfone, polyethersulfone, acrylic, orcyclic olefin copolymer (COC), biodegradable polyesters, such aspolycaprolactone (PCL), soft elastomers such as polyglycerol sebacate(PGS), or other thermoplastics. The substrates may alternatively be madeof polydimethylsiloxane (PDMS), poly(N-isopropylacrylamide), ornanotubes or nanowires formed from, for example, carbon or zinc oxide.

The upper and lower walls of the blood channel 102 a are defined by themembranes 110 a and 108 a, respectively. In some implementations, theside walls of the blood channel can be made from a substrate materialsimilar to the substrates 114 a and 116 a. The blood channel 102 a canbe coated with cytophilic or cytophobic materials to promote or preventthe growth of cells, such as vascular endothelial cells, in thechannels. The blood channel 102 a may also be coated with ananticoagulant to help prevent clotting of the blood. In someimplementations, the anticoagulant is applied to the substrate walls ofthe blood channel 102 a, but not to the walls defined by the membranes108 a and 110 a.

The convective clearance device layer 100 a is designed for use inhemofiltration. The blood channel 102 a, the infusate channel 104 a, andthe waste channel 106 a are configured such that a relatively largesurface area of the fluid flowing through the channels is exposed to themembranes 108 a and 110 a. In some implementations, the channels 102 a,104 a, and 106 a can have rectangular cross-sections, with a relativelylarge fluid interface at the membranes 108 a and 110 a, to promote fluidcommunication between the blood channel 102 a, the infusate channel 104a, and the waste channel 106 a. The channels 102 a, 104 a, and 106 a canalternatively have semicircular cross sections. In otherimplementations, the channels 102 a, 104 a, and 106 a may have any othertype of cross section, such as a substantially rectangular cross-sectionwith rounded corners, or an irregularly shaped cross-section.

Blood is introduced into an inlet 118 a of the blood channel 102 a andflows along the length of the blood channel 102 a in the directionindicated by arrow 120 a. Infusate (e.g., saline or physiologicallybalanced replacement solution) is simultaneously introduced into theinfusate channel 104 a through inlets 122 a. A transverse pressure isapplied to the infusate channel 104 a and the waste channel 106 a,causing fluid in these channels to flow in the directions indicated bythe arrows 124 a and 126 a, respectively. As blood flows through theblood channel 102 a, the transverse pressure gradient causes an infusionof infusate to flow from the infusate channel 104 a, through themembrane 108 a, and into the blood channel 102 a. The transversepressure causes fluid from the blood channel 102 a, including plasma,urea, and other waste particles, such as particle 109 a, to be forcedinto the waste channel 106 a through the membrane 110 a. Cleansed bloodcan then be collected from an outlet 128 a of the blood channel 102 a.In some implementations, waste-collecting fluid passes out of theconvective clearance device layer 100 a through outlets 130 a in thewaste collecting channel, and can then be filtered and recirculated backto the inlets 122 a of the infusate channel 104 a. Blood and infusatecan be introduced in such a way as to maintain substantially laminarflow in the blood channel 102 a. In some implementations, the infusatechannel 104 a and the waste channel 106 a can be reservoirs or fluidbaths whose volume is significantly larger than the volume of the bloodchannel 102 a. In some implementations, a dialysate can be introduced tochamber 106 a to allow diffusive transport in addition to the convectivetransport due to flow 126 a.

The membrane 110 a can be configured to allow clearance of particleshaving a molecular weight of less than about 60 kDa. Larger particlesexemplified by particle 132 a, such as blood cells, can remain withinthe blood channel. The membrane 108 a can be identical to the membrane110 a. However, in some implementations, the membrane 108 a can havepore sizes that are significantly smaller than the pore sizes of themembrane 110 a, because it is only necessary to allow fresh infusate topass through the membrane 108 a. For example, smaller pore sizes may beselected to prevent the introduction of impurities into the bloodchannel 102 a while still allowing infusate to flow into the bloodchannel 102 a. For example, a pore size less than about 0.2 μm canreduce (or substantially prevent) the passage of bacteria across themembrane 108 a. In other implementations, desirable solutes may beintroduced into the infusate channel 104 a, and the membrane 108 a canbe configured to allow the desirable solutes to pass into the bloodchannel 102 a. The membrane 108 a can be made from an impermeablematerial into which pores have been fashioned, for example by a laseretching process. Alternatively, the membrane 108 a can be constructedfrom a naturally porous material.

The pressure gradient indicated by the arrows 124 a and 126 a issubstantially constant throughout the lengths of the infusate channel104 a and the waste channel 106 a. For example, substantially constantpressure can be achieved by positioning a number of inlets 122 a alongthe length of the infusate channel 104 a. Similarly, a number of outlets130 a can be positioned along the length of the waste-collecting channel106 a. This allows the blood channel 102 a to experience a simultaneousinfusion of fluid from the infusate channel 104 a and outflow of fluidto the waste channel 106 a, which results in a substantially constantvolume of blood along the length of the blood channel 102 a. Bycontrast, in typical hemodialysis devices, forward filtration occursalong a portion of the length of the device, and back filtration occursalong a separate portion of the device, resulting in a varying fluidvolume profile along the length of the device. Achieving increasedconvective clearance in these types of devices requires a largervariance of the volume of blood along the length of the device, whichcan lead to unsafe hematocrit levels.

Hematocrit in the blood channel 102 a is preferably maintained within anacceptable range in order to ensure blood health. The substantiallyconstant volume of fluid maintained in the blood channel 102 a causes asubstantially constant hematocrit level in the blood channel 102 a.Therefore, the amount of convective clearance achieved in the convectiveclearance device layer 100 a can be increased without significantlyincreasing the risk of unsafe hematocrit levels. In someimplementations, the amount of convective clearance is proportional tothe magnitude of the transverse pressure gradient indicated by arrows124 a and 126 a. As discussed above, increasing the infusion of fluidfrom the infusate channel 104 a to the blood channel 102 a allowsincreased outflow of fluid from the blood channel 102 a to the wastechannel 106 a, while preserving the volume of fluid in the blood channel102 a. Other hemodialysis devices typically require increased channellengths, increased blood flow, and increased residence time of fluid inthe channels in order to increase the amount of convective clearance.The convective clearance device layer 100 a can therefore be used toachieve significantly higher levels of convective clearance without aneed for increasing the overall size of the convective clearance devicelayer 100 a.

The transverse pressure gradient may expose the membranes 108 a and 110a to stresses that can cause the membrane 108 a to deform towards theblood channel 102 a and can cause the membrane 110 a to deform towardsthe waste channel 106 a. To prevent significant deformation of themembranes 108 a and 110 a, the infusate channel 104 a and thewaste-collecting channel 106 a can include structural supports 112 a.The structural supports 112 a can span the width of the infusate channel104 a and the waste-collecting channel 106 a, and can be attached to themembranes 108 a and 110 a to hold them in place against the force of thefluid pressure gradient indicated by arrows 124 a and 126 a. In otherimplementations, the structural supports 112 a can substantially fillthe volume of the infusate channel 104 a and the waste channel 106 a toprovide rigidity to the channels 104 a and 106 a and reduce deformationof the membranes 108 a and 110 a. For example, the structural supports112 a can be porous mesh structures made from ceramic, carbon, polymer,or other materials. The structural supports 112 a can also be posts orridges inserted into the blood channel 102 a, the infusate channel 104a, or the waste-collecting channel 106 a. To prevent the obstruction offluid flow in the infusate channel 104 a and the waste-collectingchannel 106 a, the structural supports 112 a can be selected to havepore sizes that are larger than the pore sizes of the membranes 108 aand 110 a, so that the clearance of particles from the fluids iscontrolled only by the pore sizes of the membranes 108 a and 110 a.

In some implementations, a microfluidic convective clearance devicesimilar to the device layer 100 a can be configured such that only aportion of the fluid in the infusate channel and waste channel flowsperpendicular to the flow of fluid in the blood channel, while theremaining portion of fluid in the infusate channel and waste channelflows parallel to the flow of fluid in the blood channel. An example ofsuch a device is shown in FIG. 1D

FIG. 1D is a cross-sectional view of a second microfluidic convectiveclearance device 100 b for use in hemofiltration, according to anillustrative implementation. The device 100 b includes many of thefeatures of the device layer 100 a shown in FIG. 1C. For example, thedevice 100 b includes a blood channel 102 b, an infusate channel 104 b,and a waste-collecting channel 106 b. The channels are defined by wallsmade from substrate materials 114 b and 116 b and membranes 108 b and110 b, and can include structural supports 112 b. Fluid can beintroduced into an inlet 140 b of the infusate channel 104 b. Thepressure in the infusate channel 104 b causes some of the fluid to passthrough the membrane 108 b and into the blood channel 102 b, in thedirection shown by the arrow 127 b. The remaining portion of the fluidin the infusate channel 104 b can travel parallel to the blood channel102 b along the length of the channel 104 b, as shown by the arrow 125b, and can be collected at an outlet 142 b.

Undesired particles, such as particle 109 b, can also pass through themembrane 110 b into the waste-collecting channel 106 b. In someimplementations, additional waste-collecting fluid can be introduced atan inlet 146 b of the waste-collecting channel 106 b, causing fluidwithin the waste-collecting channel 106 b to flow in the direction shownby arrow 131B. Waste-collecting fluid can be collected from the outlet144 b, and purified blood can be collected from the outlet 128 b as theblood flows along the blood channel 102 b in the direction shown by thearrow 120 b. In some other implementations, the waste-collecting fluidcan be introduced such that the fluid in the waste-collecting channelflows in a direction opposite the direction shown by arrow 131C. In someimplementations, the waste collecting fluid introduced can be adialysate to provide diffusive clearance in addition to convectiveclearance.

FIG. 1E is a cross-sectional view of a third microfluidic convectiveclearance device 100 c for use in hemofiltration, according to anillustrative implementation. The device 100 c includes many of thefeatures of the device layer 100 a shown in FIG. 1C. For example, thedevice 100 c includes a blood channel 102 c, an infusate channel 104 c,and a waste-collecting channel 106 c. The channels are defined by wallsmade from substrate materials 114 c and 116 c and membranes 108 c and110 c, and can include structural supports 112 c. Unlike the device 100b of FIG. 1D in which the an infusate channel 104 b and a wastecollecting channel 106 b run parallel to the blood channel 102 b, theinfusate channel 104 c and waste-collecting channel 106 c of the device100 c are oriented perpendicular to the blood channel 102 c.

Fluid can be introduced into an inlet of the infusate channel 104 c inthe direction shown by the vector 134 c (e.g., directed into the page).The pressure in the infusate channel 104 c causes some of the fluid topass through the membrane 108 c and into the blood channel 102 c, in thedirection shown by the arrow 150 c. The remaining portion of the fluidin the infusate channel 104 c can travel along the length of the channel104 c, in the direction of the vector 134 c, and can be collected at anoutlet.

Higher pressure is maintained in the blood channel 102 c as compared tothe waste-collecting channel 106 c, causing some of the fluid in theblood channel 102 c to pass into the waste-collecting channel 106 cthrough the membrane 110 c, in the direction shown by the arrow 152 c.Undesired particles, such as particle 109 c, can also pass through themembrane 110 c into the waste-collecting channel 106 c. In someimplementations, additional waste-collecting fluid can be introduced atan inlet of the waste-collecting channel 106 c, causing fluid within thewaste-collecting channel 106 c to flow in the direction shown by vector136 c (e.g., out of the page). Waste-collecting fluid can be collectedfrom an outlet of the waste-collecting channel, and purified blood canbe collected from the outlet 128 c of the blood channel 102 c as theblood travels along the blood channel 102 c in the direction shown byarrow 120 c. In some other implementations, the waste-collecting fluidcan be introduced such that the fluid in the waste-collecting channelflows in a direction opposite the direction shown by vector 136 c (e.g.,parallel to the direction of fluid flow in the infusate channel 104 c.In some implementations, the waste collecting fluid introduced can be adialysate to provide diffusive clearance in addition to convectiveclearance.

FIGS. 2A-2F depict the device of FIG. 1C at various points in themanufacturing process. FIG. 2A shows a rectangular block of substratematerial 216. The substrate material can be used to form either theinfusate channel or the waste-collecting channel of FIG. 1C, as both ofthese channels are very similar. Therefore, the processes discussed inconnection with the manufacture of either channel will also be useful inthe manufacture of the other. The substrate material 216 can be any ofthe materials described above in connection with the substrates used inthe device of FIG. 1C, such as thermoplastics, biodegradable polyesters,or nanotubes or nanowires formed from, for example, carbon or zincoxide. The substrate material 216 can be a solid block whose dimensionsare selected to provide sufficient volume to form the infusate channelor waste collecting channel of FIG. 1C.

FIG. 2B shows a cross-sectional view of the substrate 216 of FIG. 2Aafter it has been hollowed out to form a channel 206. For example, thechannel 206 can be used as the infusate channel or the waste-collectingchannel of FIG. 1C. The channel 206 can be created in the substrate 216by any method of material removal, such as an etching or millingprocess. The result is the hollow channel 206 suitable for carryinginfusate or waste-collecting fluid, surrounded on three sides by thesubstrate material 216. The fourth side of the channel will be formed bya membrane, so the substrate material 216 is completely removed fromthis side.

FIG. 2C shows a cross-sectional view of the substrate 216 and thechannel 206. Also shown are openings 230 leading into the channel 206.The openings 230 can be used as the infusate inlets or waste fluidoutlets described in FIG. 1C. In some implementations, the openings 230are positioned evenly across the surface of the substrate 216, tofacilitate an even pressure gradient along the length of the channel206. Although five openings 230 are shown in FIG. 2C, any number ofopenings 230 can be present. In some implementations, the openings canbe created by a chemical or laser etching, drilling, or milling processin which material is removed from the surface of the substrate 216. Theshape of the openings can be circular, rectangular, or any other shapesuitable for introducing fluid into the openings (e.g., into the inletsof the infusate channel of FIG. 1C) or extracting fluid from theopenings (e.g., from the outlets of the waste-collecting channel of FIG.1C).

FIG. 2D shows a cross-sectional view of the substrate material 216,channel 206, and openings 230. Also shown in FIG. 2D are structuralsupports 212 coupled to the substrate 216. The structural supports 212are intended to reinforce the structural integrity of the channel 206and to prevent deformation of a membrane that will be added later in theprocess, so the structural supports 212 are preferably made from asubstantially rigid material such as a polymer or a metal. As shown inFIG. 2D, the structural supports can be aligned with the direction offluid flow in the channel 206 (see arrows 124 a and 126 a of FIG. 1C),in order to reduce interference with the flow of infusate orwaste-collecting fluid in the channel 206. In other implementations, thestructural supports 212 can occupy a substantial portion of the channel206. For example, the structural supports 212 can be made from a porousmaterial that allows fluid to flow through the channel 206. Thestructural supports 212 can be coupled to the substrate 216 by amechanical joint or by a medical grade adhesive suitable for use in afluid channel.

FIG. 2E shows a cross-sectional view of the substrate 216 configured asin FIG. 2D, with the addition of a membrane 210. The membrane 210 can beused as either of the membranes 108 a or 110 a of FIG. 1C. In someimplementations, the membrane 210 is selected to allow clearance ofparticles having a molecular weight smaller than about 60 kDa. Themembrane 210 is coupled to the structural supports 210 in order toprevent the membrane 210 from deforming under the pressure of the fluidflowing through the channel 206. The membrane 210 can be joined to thestructural supports 212 by a mechanical fastener or by an adhesive.

FIG. 2F shows the features of the infusate channel of FIG. 1C. Asdiscussed above, the elements shown in FIG. 2E can be used to formeither the infusate channel or the waste-collecting channel of FIG. 1C.Therefore, structure of FIG. 2F can be manufactured by repeating theprocess described in connection with FIGS. 2A-2E to produce a secondstructure. The structure of FIG. 2F is similar to the structure shown inFIG. 2E, but rotated 180 degrees such that the openings 230 of FIG. 2Fare opposed to the openings of FIG. 2E.

FIG. 2G shows a pair of substrate walls 217. The substrate walls areparallel to each other and define the side walls of a channel 202, whichcan be used as the blood channel of FIG. 1C. The channel 202 is open onits top and bottom sides at this step in the process, but willeventually be defined by the membranes 210 as shown in FIG. 2H.

FIG. 2H shows the final step of the manufacturing process formanufacturing the device of FIG. 1C. The membranes 210 of the twoinstances of channel 206 (depicted in FIGS. 2E and 2F) are joined to thesubstrate walls 217 (depicted in FIG. 2G) to form the channel 202, whichis defined on its upper and lower walls by the membranes 210, and on itssides by the substrate walls 217 as shown in FIG. 2G. The substratewalls 217 are not visible in the cross-sectional view of FIG. 2H. Thechannel 202 can be used as the blood channel of FIG. 1C, while thechannels 206 can be used as the infusate channel and waste-collectingchannel. In other implementations, the manufacturing process can includea net shape molding process.

FIG. 3 depicts a block diagram of a control system 300 that can be usedwith the devices of FIGS. 1C-1E. The control system 300 includes anelectronic processor 302 in communication with fluid pressure sensors304, fluid flow sensors 306, a blood introduction device 308, a filtrateintroduction device 309 and an infusate introduction device 310. Becausethe devices of FIGS. 1C-1E are intended for use in hemofiltration,promoting health of the patient's blood as it flows through the bloodchannel is important. The control system 300 can be used to ensure thatthe patient's blood remains healthy.

Pressure sensors 304 and flow sensors 306 can be placed inside the bloodchannel. In some implementations, the physical shape of the fluidpressure sensors 304 and the flow sensors 306 can be selected to reduceinterference with the flow of blood in the blood channel. For example,the pressure sensors 304 and the flow sensors 306 can have a small sizeor a hydrodynamic shape in order to promote laminar fluid flow. Duringoperation of the device, the pressure sensors 304 and the flow sensors306 can measure the pressure and flow characteristics in the bloodchannel and can transmit the measurements to the processor 302. Thepressure sensors 304 and the flow sensors 306 can report measurementscontinuously, or at predetermined time intervals.

The processor 302 can determine whether the pressure and flow in theblood channel are suitable for maintaining blood health. The processor302 can compare the measurements taken by the pressure sensors 304 andthe flow sensors 306 to predetermined ranges that are deemed to be safefor blood. If the pressure or flow rate is outside of the acceptablerange, the processor can attempt to correct the problem by transmittingsignals to the blood introduction device 308, the filtrate introductiondevice 309, or the infusate introduction device 310. For example, theprocessor can reduce the flow rate in the blood channel by triggeringthe blood introduction device 308 (e.g., a pump) to decrease the amountof blood introduced at the inlet of the blood channels. The processorcan also respond to an unacceptably high fluid pressure in the bloodchannel by triggering the infusate introduction device 310 to reduce therate at which infusate is introduced at the inlets to the infusatechannel. In another example, the processor can trigger the infusateintroduction device 310 to increase the rate at which infusate isintroduced (e.g., to decrease the hematocrit in the blood channel). Inanother example, the filtrate introduction device 309 can control thepressure differential between the blood and filtrate channels bydecreasing or increasing the amount of filtrate introduced at the inletof the filtrate channels. In some implementations, the processor 302 cancontrol the blood introduction device 308, the filtrate introductiondevice 309, and the infusate introduction device 310 to achieve adesired hematocrit profile in the blood channel. For example, theprocessor 302 can control the blood introduction device 308 and theinfusate introduction device 310 to maintain a constant hematocrit levelthroughout the blood channel. Alternatively, in some implementations,the processor 302 can control the blood introduction device 308 and theinfusate introduction device 310 to create a hematocrit profile thatvaries along the length of the blood channel.

FIG. 4 is a flow diagram of a method 400 for filtering liquid containingan analyte, according to an illustrative implementation. The method 400includes the steps of introducing a first liquid solution (step 402),introducing infusate (step 404), introducing waste-collecting fluid(step 406), and collecting the cleansed liquid (step 408). In step 402,a first liquid containing an analyte is introduced into an inlet of oneor more first channels. In some implementations, the fluid is blood thathas been extracted from a patient for filtration. The analyte can be anyundesirable substance, such as urea, uric acid, creatinine, or othertoxins or pathogens. The first channels can have a height in the rangeof about 50 microns to about 500 microns, about 100 microns to about 400microns, or about 200 microns to about 300 microns. The first channelscan have a width in the range of about 50 microns to about 900 microns,about 200 microns to about 750 microns, about 350 microns to about 600microns, or about 350 microns to about 450 microns. The length of thefirst channels can be in the range of about 3 centimeters to about 25centimeters, about 10 centimeters to about 25 centimeters, or about 15centimeters to about 20 centimeters. In some implementations, if bloodis to be introduced into the first channel, the first channel caninclude an anticoagulant coating on its inner walls and can beconfigured to maintain wall shear rates in the range of about 100inverse seconds to about 3500 inverse seconds.

The method 400 includes the step of introducing infusate into an inletof at least one second channel (step 404). The second channel iscomplementary to one or more of the first channels, and the infusate isintroduced into the second channel such that it flows in a directionperpendicular to the direction of the first liquid in the first channel.The second channel is separated from the one or more complementary firstchannels by a first permeable membrane, which allows some of theinfusate to be transported from the second channel into the firstchannel.

The method 400 includes the step of introducing waste-collecting fluidinto an inlet of at least one third channel (step 406). The thirdchannel is complementary to one or more of the first channels, and thethird channel is separated from the one or more complementary firstchannels by a second permeable membrane, which allows some of theanalyte to be transferred from the first channel to the third channel.In some implementations, introducing the first liquid (step 402),introducing the infusate (step 404), and introducing thewaste-collecting fluid (step 406) can occur simultaneously andcontinuously. The waste-collecting fluid can be introduced such that thepressure in the third channel is less than the pressure in the adjacentfirst channel, which can result in an outflow of fluid form the firstchannel to the third channel. In some implementations, the wastecollecting fluid introduced can be a dialysate to provide diffusiveclearance in addition to convective clearance.

In some implementations, introducing the first liquid (step 402),introducing the infusate (step 404), and introducing thewaste-collecting fluid (step 406) can occur simultaneously andcontinuously. For example, the first liquid, infusate, andwaste-collecting fluid can be flowed continuously through theirrespective channels. Infusate is transported from the second channel tothe first channel through the first membrane. The infusion of infusateinto the first channel allows an outflow of fluid from the first channelto the third channel through the second membrane while maintaining afluid balance in the first channel. Waste particles, such as urea, uricacid, or creatinine, are also transported through the second membraneand into the third channel. The waste-collecting fluid in the thirdchannel then carries the waste particles away from the first channel.

As discussed above, the first liquid can be blood that has beenextracted from a patient for cleansing. The ratio of liquid to red bloodcells in the first channel can be substantially constant along itslength so as to maintain substantially constant hematocrit in the blood.Blood health can also be preserved by maintaining laminar flow in thefirst channel and holding fluid shear rates in a range of about 100 toabout 3500 inverse seconds.

The method 400 can also include the step of collecting cleansed liquidfrom an outlet of the one or more first channels (step 408). As theliquid is transported along the length of the first channel from theinlet to the outlet, some of the waste particles in the liquid areremoved from the first channel through the second membrane, as discussedabove. Therefore, when the liquid reaches the outlet of the firstchannel, it has a substantially smaller concentration of wasteparticles. If the fluid is blood that has been extracted from a patient,the filtered blood can be collected at the outlet of the first channeland can then be returned to the patient.

FIGS. 5A, 5B, 6A-10, and 13 illustrate example microfluidic convectionclearance devices. Each of the devices described in relation to FIGS.5A, 5B, 6A-10, and 13 can form a layer 102 of the device illustrated inFIG. 1A. FIG. 5A illustrates a cross-sectional view of a microfluidicconvective clearance device 500 for use in hemofiltration. The device500 includes an infusate channel 501 and a filtrate channel 502 oneither side of a blood channel 503. The blood channel 503 is separatedfrom the infusate channel 501 and from the filtrate channel 502 by amembrane 504 (also referred to as an interchannel flow barrier). Thefiltrate channel 502 is in fluid communication with a filtrate reservoir506, and the infusate channel 501 is in fluid communication with aninfusate reservoir 505 via manifolds such as those described above inrelation to FIG. 1A. A pump 509 is placed in-line with the infusatereservoir 505 and the filtrate reservoir 506. A valve 510 is placedin-line with each of the pumps 509. The substrate defining infusatechannel 501, the substrate defining filtrate channel 502, and thesubstrate defining blood channel 503 can form a layer 102 of the device100 illustrated in FIG. 1A.

The fluid exiting the infusate channel 501 and the filtrate channel 502return to the infusate reservoir 505 and the filtrate reservoir 506,respectively, and can be recycled through the device 500. The infusatereservoir 505 includes an inlet 507 where fresh infusate is added to thedevice 500. The filtrate reservoir 506 includes an outlet 508 wherecollected filtrate is removed from the device 500. In otherimplementations, the inlet 507 and the outlet 508 are placed at anylocation along their respective fluidic circuits. In someimplementations, the filtrate channel 502 and the infusate channel 501are not coupled to dedicated reservoirs. In these implementations, thetubing coupling the outlet of each channel back to the inlet of thechannel functions as a fluid reservoir.

In general, the device 500 performs hemofiltration by flowing bloodthrough the blood channel 503. Initially, the blood in the blood channelincludes a plurality of particles 109, which can include urea, middlemolecules, and other waste molecules to be filtered out of the blood.Infusate is flowed into the channel 501, creating a pressure gradient inthe infusate channel 501. The infusate is pumped into the infusatechannel 501 at a rate such that the pressure drop in the the infusatechannel 501 is controlled relative to the pressure drop in the bloodflow channel 503. The infusate is pumped into the infusate reservoir 505through the inlet 507 at a rate such that the pressure at any givenpoint along the infusate channel 501 is greater than the pressure in theblood flow channel 503, resulting in a transmembrane pressuredifferential. The transmembrane pressure forces fresh infusate 514through the membrane 504, and into the blood channel 503. A pressuredifferential between the blood channel 503 and the filtrate channel 502causes a flow 515 from the blood channel 503 and into the filtratechannel 502. The flow 515 carries the particles 109 through the secondmembrane 504 and into the filtrate channel 502. The particles 109 can beremoved from the filtrate in the filtrate reservoir 506. In someimplementations, the filtrate is not filtered and a portion of thefiltrate is removed from an outlet of the filtrate fluid circuit tocreate a vacuum that helps pull the particles 109 and other fluids fromthe blood channel 503 into the filtrate channel 502. For example, afluid of volume substantially equal to the amount of fluid desired topass into the filtrate channel 502 from the blood channel 503 isremoved. In some implementations, between about 5% and about 40%, about5% and about 20%, or about 10% and about 20% of the fluid flow rate offluid flowing through the filtrate channel 502 is removed through eachcycle.

In device 500, as the blood flows down the length of the blood channel503, the waste particles 109 are removed from the blood. The blood isreinfused with the fresh infusate from the infusate channel 501 as theblood travels down the blood channel 503. The reinfusion maintains bloodvolume and maintains the blood hematocrit at a constant level. In otherimplementations, the reinfusion rates are controlled to vary thehematocrit level according to a doctor's prescription. The amount ofconvective transport attained is proportional to the amount of fluidintroduced to the infusate channel 501 and the amount of fluid removedfrom the filtrate channel 502 through the outlet 508. In someimplementations, pressures within the infusate channel 501, bloodchannel 503, filtrate channel 502, or any combination thereof arealtered to control the net and total convection that occurs. In someimplementations, the membrane properties can be adjusted to limit whichmolecules cross the membrane based on a molecular weight cut off orother properties of the membranes 504. For example, the membrane couldbe etched (to increase diffusion and convection through the membrane) orsealed (to decrease diffusion and convection through the membrane) tochange the membrane's transport properties.

Each of the infusate channel 501 and the filtrate channel 502 include avalve 510 in-line with the pump 509. The valve 510 is one example of anactive pressure control feature, which are also referred to herein ascontrollable flow control devices. Pressure control features can beactive (e.g., the controllable valve 510) or passive (e.g., a fixedvariation in channel diameter or a static porous membrane). The pressurecontrol features can be placed toward the inlet and/or outlet (oranywhere along the fluidic circuit) of any of the infusate channel 501,the blood channel 503, and the filtrate channel 502. Referring back tothe valves 510, each valve 510 is configured to adjust the pressure ofthe fluid between the outlet of the pump 509 and the inlet of therespective infusate channel 501 or filtrate channel 502. The valves 510can also be configured to control the flow rate of the fluid enteringthe infusate channel 501 and the filtrate channel 502. The pressureentering the infusate channel 501 and the filtrate channel 502 can beset to control the pressure drop along each of the channels and providethe desired pressure profile along the infusate channel 501 and thefiltrate channel 502. In some implementations, one of or neither of theinfusate channel 501 and the filtrate channel 502 include a valve 510.In some implementations, the valve 510 is a variable, proportional flowvalve. Referring to FIG. 3, the valve 510 can be controlled by thecontrol system 300. For example, the control system 300 can set thevalve 510 to different operational states that constrict or dilate aflow path through the valve 510.

Each of the substrates in which the infusate channel 501, the filtratechannel 502, and the blood channel 503 are defined in a thermoplasticsuch as, but not limited to, acrylic, polystyrene, polycarbonate. Eachof the filtrate and infusate channels have a length of between about 5cm and about 30 cm, about 10 cm and about 30 cm, about 15 cm and about30 cm, or between about 20 cm and about 30 cm. The width of the filtrateand infusate channels are between about 300 μm and about 1000 μm orbetween about 750 μm and 1000 μm. The height of the channels is betweenabout 10 μm and 500 μm or between about 10 μm and about 80 μm. In someimplementations, each layer 102 includes a single infusate channel thatspans a plurality of the blood flow channels. A device with a single,wide infusate channel can be used when the infusate in introduced to theblood through controlled infusion areas, for example, the microfluidicconvective clearance device described below in relation to FIG. 8A.

In some implementations, one or more components of the device 500 aredisposable and configured to withstand sterilization. For example,because the infusate flowing through the infusate channel 501 comes intocontact with the blood in the blood channel 503, the substrates of thedevice 500 defining the infusate channel 501 and blood channel 503 maybe sterilized prior to use and be disposed of after use.

Each of the infusate channel 501, the blood channel 503, and thefiltrate channel 502 have a pressure profile. The pressure profiledefines how the pressure changes along the length of each of thechannels, which in turn defines the pressure differentials between thechannels. This pressure differential can also be called thetrans-membrane pressure. In some implementations, if the trans-membranepressure (e.g., the relative pressure difference across a membrane) istoo high for a given membrane, the membrane between the blood and thefiltrate channels can clog with the particulate from the blood. Theclogging of the membrane can result in a degradation of the performanceof the device as fluid and particles cannot pass from the blood channel503 to the filtrate channel 502. In some implementations, if thetrans-membrane pressure differential is too low at any location alongthe length of the channel, the device underutilizes its ability to clearparticles from the blood.

Maintaining a controlled transmembrane pressure (or trans-interchannelbarrier pressure) along the length of the channels enables substantiallythe entire length of the channels to contribute to the convectiveclearance. Controlling the transmembrane pressure also protects areas ofmembrane from high transmembrane pressures that can damage the membrane.Controlling variation in trans-membrane pressure along the length of thechannel within 50% provides for efficient use of the membrane with thefull length of the membrane contributing to overall convective clearancewhile not sacrificing durability. This enables the use of less membranewithin the device while promoting greater durability. In a traditionaldevice, the transmembrane pressure varies widely along the length of thefiber or channel due to the countercurrent flow of dialysate and therelatively low pressure drop that results due to the open geometry ofthe dialysis chamber. This can result in variation in transmembranepressure along the length of the fiber or channel of over 100%. Forthese devices, the transmembrane pressure is high at the channel inletsand low at the channel outlets. If the pressure profiles are controlledto prevent high transmembrane pressure from damaging the membrane at theproximal portion of the membrane, the distal portion of the membrane isexposed to low pressures and does not provide significant convectiveclearance. If the transmembrane pressure is allowed to exceed safelevels for the membrane to enable the distal portion of the membrane tocontribute to convective clearance, the proximal portion of the membranewill foul and lead to premature failure of the filter.

As described above, lower variation in transmembrane pressure along thelength of the channel can provide for efficient use of the membranealong the full length of the membrane. For example, the pressuredifference between any two of the channels in the convective clearancedevice is controlled such that the pressure difference does not vary bymore than 50% of the pressure difference between the two channels, andin other implementations the pressure difference is controlled atpredetermined locations, such as at the inlet (or other upstreamportion) of the channels. In some implementations, the pressuredifference varies between about 0% and about 40%, about 0% and about30%, about 0% and about 20%, about 0% and about 15%, about 0% and about10%, or about 0% and about 5%.

In some implementations, the pressure profile at the inlet or outlet ofthe channels is controlled to prevent clogging of the membrane. Forexample, if the transmembrane pressure at a location is too high, themembrane can become clogged. However, a transmembrane pressure that istoo low can result in lower convective flow performance. In someimplementations, the pressure difference between any two of the channelsin the convective clearance device is controlled such that the pressuredifference along the length of the channels does not vary by more than50% of the average pressure difference between the two channels. In someimplementations, the pressure difference varies between about 0% andabout 40%, about 0% and about 30%, about 0% and about 20%, about 0% andabout 15%, about 0% and about 10%, or about 0% and about 5% of theaverage pressure difference between the two channels.

In some implementations, complementary pressure control featuresmaintain a substantially constant pressure along the length of eachchannel. For example, the pressure control features may compensate forthe loss or addition of fluid volume to a channel by decreasing orincreasing the cross-sectional area of a channel. In someimplementations, the pressure control features prevent or reduce apressure drop that otherwise would occur along the length of theinfusate channels by reducing the effective resistance through thechannel. Similarly, increases in pressure along the filtrate channel canbe reduced or prevented by reducing the effective resistance through thechannel. In some implementations, the complementary pressure controlfeatures maintain parallel pressure profiles by maintaining asubstantially constant pressure difference between adjacent channels. Inthese implementations, the pressure changes in each of the channelsalong their respective lengths; however, the transmembrane pressuredifferential remains substantially constant because each of the channelsexperience the same pressure drop along their respective lengths. Insome implementations, the transmembrane pressure is deliberatelydeviated from substantially constant to adjust the amount of filtrationor infusion that occurs upstream versus downstream with respect to theflow in the channels. The pressure control features can be added to theinfusate channel, the filtrate channel, the blood channel, themembranes, or a combination thereof.

Controlling the pressures along the length of the channels can improvethe performance of the device for convective flow. The devices describedherein include pressure control features configured to control thetransmembrane pressure between adjacent channels. The channels of thedevices can include complementary pressure control features such thatthe pressure profiles for each of the channels remain parallel, orsubstantially parallel, along the length of the channels. For example,during the operation of the devices described herein the infusatechannel can lose pressure along its length as fluid flows into the bloodchannel from the infusate channel. At the same time, the filtratechannel can gain pressure along its length as fluid volume flows fromthe blood channel and into the filtrate channel. The infusate channelcan include a first set of pressure control features to compensate forthe decrease in fluid and the filtrate channel can include a second setof pressure control features that are complementary to the first tocompensate for the increase in fluid in the filtrate channel. Becausethe transmembrane pressure differential is a relative value, thetransmembrane pressure can be controlled in a number of ways.

In addition to adding pressure control features to one or more of thechannels and membranes in the convective clearance device, in someimplementations the pressure control feature includes flow control logicthat controls the rate of flow through one or more of the channel bycontrolling the throughput of the pumps 509. According to fluidmechanics, if flow increases through a known restriction (e.g., achannel), then the pressure differential required to cause that flowincreases. In this way, the flow from the pump 509 can be increased toincrease the pressure drop from inlet to outlet. In the same way, theflow from the pump 509 can be decreased to decrease the pressure dropfrom inlet to outlet. The pressure drop defines the bounds of thepressure profile within a channel. The rate at which the pumps 509 flowfluid through the channels can be automatically or manually adjusted tomaintain a desired pressure profile through the channels of theconvective clearance device. For example, the blood can be flowedthrough the blood flow channel at a rate safe for blood (e.g., a ratethat causes minimal trauma and shear to the red blood cells). The rateof the infusate through the infusate channel may be decreased orincreased until the pressure profile of the infusate is similar in slopeto the pressure profile of the blood. The rate of the filtrate throughthe filtrate channel may be increased or decreased until the pressureprofile of the filtrate is similar in slope to the pressure profile ofthe blood. Pressure sensors can be added to the proximal and distalportions of channels as required to provide feedback for adjusting thepressure profiles.

FIG. 5B illustrates a cross-sectional view of another microfluidicconvective clearance device 513 for use in hemofiltration. The device513 is similar to the device 500 described above in relation to FIG. 5A.The device 513 includes an infusate channel 501 and a filtrate channel502 on either side of a blood channel 503. The blood channel 503 isseparated from the infusate channel 501 and from the filtrate channel502 by a membrane. A recirculating pump 509 is placed in-line with theinfusate channel 501 and filtrate channel 502. The device 513 alsoincludes a four diaphragm chambers 511. An influx pump 516 is in-linewith the infusate channel 501 and pumps additional infusate into theinfusate channel 501. The device 513 also includes an outflow pump 517in-line with the filtrate channel 502. The outflow pump 517 isconfigured to draw filtrate out of the filtrate channel 502. Thediaphragm chambers 511, influx pump 516, outflow pump 517, andrecirculating pump 509 are each examples of active pressure controlfeatures.

The diaphragm chambers 511 are placed towards the inlets and outlets ofthe infusate channel 501 and the filtrate channel 502. The diaphragmchambers 511 are configured to set a predetermined pressure at each ofthe inlets and outlets to which they are coupled. Each of the diaphragmchambers 511 are coupled with a regulator and a pressure source.Increasing the pressure fed into the diaphragm chamber 511, via theregulator and the pressure source, increases the pressure in the fluiddirectly as it acts across the diaphragm. Decreasing the pressure fedinto the diaphragm chamber 511, via the regulator and the pressuresource, decreases the pressure in the fluid directly as it acts acrossthe diaphragm. The recirculating pump 509 acts to transfer fluid fromthe lower pressure distal diaphragm chamber to the higher pressureproximal diaphragm chamber. The recirculating pump 509 can be controlledas a variable flow rate pump or activated intermittently when fluidvolume in the proximal diaphragm chamber falls below a predeterminedlevel. The amount of flow through the channel is determined by thegeometry of the channels and the pressure conditions applied by thediaphragm chambers 511.

The influx pump 516 is configured to flow fresh infusate into theinfusate channel 501. The outflow pump 517 is configured to flow anequivalent amount of filtrate out of the filtrate channel 502. Byreplenishing the infusate channel 501 and drawing the same volume offluid from the filtrate channel 502, the influx pump 516 and the outflowpump 517 can maintain and control the hematocrit level within the bloodchannel of the device 513.

FIG. 5C illustrates a graph 550 of an example pressure profile of eachof the channels of device 500. The channel pressure is plotted along they-axis and the channel position is plotted along the x-axis. FIG. 5Cillustrates, assuming the length of the device 500 is L, that at theinlet to the infusate channel pressure is about 1200 mmHg, at the inletto the blood channel the pressure is about 1000 mmHg, and at the inletto the filtrate channel the pressure is about 800 mmHg. At eachchannel's outlet (channel position=L) the infusate channel pressure isabout 200 mmHg, the blood channel pressure is about 0 mmHg, and thefiltrate channel pressure is about −200 mmHg. In some implementations,the pressure difference between each of the channels is about 200 mmHgalong the entirety of the channels. In other implementations, thepressure difference is between about 50 mmHg and about 400 mmHg, about100 mmHg and about 350 mmHg, about 150 mmHg and about 300 mmHg, or about200 mmHg and about 250 mmHg. In some implementations, the initialpressure of the blood channel is between about 400 mmHg and about 1200mmHg, the initial pressure of the infusate channel is between about 600mmHg and about 1400 mmHg, and the initial pressure of the filtratechannel is between about 200 mmHg and about 1000 mmHg. In someimplementations, the final pressure of the blood channel is betweenabout −200 mmHg and about 200 mmHg, the final pressure of the infusatechannel is between about 0 mmHg and about 400 mmHg, and the finalpressure of the filtrate channel is between about −400 mmHg and about 0mmHg. As illustrated each of the pressure profiles each have the sameslope and are parallel to one another. In some implementations, asillustrated in FIG. 5C, the slope of the pressure profiles is constantand the pressure profiles are linear.

The slope of the pressure profiles, the distance between the pressureprofiles, and the shape of the pressure profiles can be controlled usingthe pressure control features described herein. For example, for theconvective clearance device generating the graph 550, the blood mayfirst be flowed through the convective clearance device. As describedabove, the rate of flow of the infusate and filtrate through thechannels is adjusted to generate the desired pressure differentialbetween the infusate and blood channels and the filtrate and bloodchannels. For example, the infusate may be flowed through the convectiveclearance device channels at a relatively lower or higher rate comparedto the blood and the filtrate may be flowed through the convectiveclearance device at a relative higher or lower rate compared to theblood. These flow rates can depend on the cross section area of thechannels. In relation to FIG. 5C, the rate of flow of the infusate andfiltrate through the channels influences the slope of the respectivepressure profiles on the graph 550. The flows through the filtrate andinfusate channels are controlled by pumps 509 or other pressure controlfeature. The flow of the infusate into the inlet 507 and the flow of thefiltrate out of the outlet 508 influence the vertical position of therespective pressure profiles on the graph 550. The slopes and/or shapesof the infusate and filtrate channels can also be tuned using one ormore of the pressure control features described herein. The verticalpositions of the pressure profiles can be controlled by additionalpumps. For example, additional pumps at the outlet 508 or inlet 507 canbe used to draw a net pressure differential between infusate and bloodor filtrate and blood channels. As illustrated on the graph 550, a 200mmHg net vacuum is applied to the filtrate channel. The vacuum shiftsvertical position of the filtrate pressure profile down, enabling thefiltrate pressure profile to match the blood pressure profile in slope,yet have an overall lower pressure resulting in flow from blood throughmembrane into the filtrate. The slope of the pressure profiles canfurther be adjusted by varying the resistance to flow through thechannel or the resistance to flow through the interchannel flow barriersalong the length of the channels. As described below, additionalpressure control features can be added to the filtrate channels,infusate channels, the membranes, or any combination thereof to furtheralter the shape of the pressure profiles.

FIG. 5D illustrates a graph 560 of another example pressure profile ofeach of the channels in an example convective clearance device. Asillustrated, the example pressure profiles of the filtrate channel andinfusate channels are stair-stepped, and the blood channel pressureprofile is substantially linear. The pressure in each of these channelsmay stay relatively constant and then step down at predeterminedpositions along the length of the channel. The step down in pressure mayoccur where the channel includes a pressure control feature. Forexample, as described further below, the complementary pressure controlfeatures may include a decreasing cross-sectional area in the infusatechannel and an increasing cross-sectional area in the filtrate channel.The cross-sectional area of the infusate and filtrate channel of theexample convective clearance device used to generate the graph 560 maychange at two locations—resulting in a down-step in on the pressureprofile at those locations of the changes in cross-sectional area. Forexample, the complementary pressure control feature in the infusate andfiltrate channels may include individual infusate and filtrate zones. Asdescribed above in relation to the linear pressure profiles, thecomplementary pressure control features control the pressure differencebetween adjacent channels. In some implementations, the blood channelalso includes a stair-stepped pressure profile.

In some implementations, the pressure profiles of the filtrate, blood,and infusate are substantially linear; however, the control systemcontrols the pressure control features to maintain differenttransmembrane pressures at the proximal and distal ends of theconvective clearance device. For example, the control system, via thepressure control features, can manipulate the slope of one of thefiltrate, blood, and infusate pressure profiles to generate pressureprofile biases toward the inlet or outlet of the device. In a“post-dilution bias,” the slope of the pressure profiles of the infusatechannel and the filtrate channel are less steep than the slope of thepressure profile of the blood channel. In contrast, in a “pre-dilutionbias” the slopes of the pressure profile of the infusate channel and thefiltrate channel are more steep than the slope of the pressure profileof the blood channel. The slope of the pressure profiles, the distancebetween the pressure profiles, and the shape of the pressure profilescan be controlled using the pressure control features described herein.

In some implementations, in a post-dilution bias configuration, thepressure control features maintain a substantially constant pressuredifference between the pressures within the infusate channel and thefiltrate channel, which makes the infusate pressure profile and thefiltrate pressure profile substantially parallel. In the post-dilutionbias configuration, the trans-interchannel flow barrier pressuredifference between the infusate and blood channels is less toward thebeginning of the device and greater toward the end of the device. Thetrans-interchannel flow barrier pressure difference between the filtrateand blood channels is greater toward the beginning of the device andless toward the end of the device. In this configuration less infusatefluid infuses into the blood at the beginning of the device, resultingin a higher concentration of solutes passing into the filtrate chamberalong the length of the device. In some implementations, thepost-dilution bias configuration can provide an overall greater amountof convective clearance when compared to the pre-dilution biasconfiguration.

In a pre-dilution bias configuration, the transmembrane pressuredifference between the infusate and blood channels is greater toward theinlet of the device and less toward the outlet of the device. Incontrast, the transmembrane pressure difference between the filtrate andblood channels is less toward the inlet of the device and greater towardthe outlet of the device. In this configuration, more infusate fluidinfuses into the blood toward the inlet of the device, but a lowerconcentration of solutes passes into the filtrate chamber from the bloodalong the length of the device. The lower concentration of solutespassing into the filtrate chamber can result in an overall lower amountof convective clearance when compared to the post-dilution biasconfiguration, but the pre-dilution bias configuration can result in alower average hematocrit within the device and an increased reliability.

FIG. 5E illustrates a graph 570 of another example pressure profile ofeach of the channels in an example convective clearance device. Asillustrated, the example pressure profiles the of infusate and filtratechannels are substantially parallel. The magnitude of the slope of theblood channel's pressure profile is more steep (e.g., greater) than themagnitude of the slope of the infusate and filtrate's pressure profile.As, illustrated the different slopes cause a post-dilution bias, asthere is a greater pressure difference between the blood and filtratepressure profiles towards the inlet of the convective clearance devicewhen compared to the outlet of the convective clearance device.

FIG. 5F illustrates a graph 580 of another example pressure profile ofeach of the channels in an example convective clearance device. Asillustrated, the example pressure profiles of the infusate and filtratechannels are substantially parallel. The magnitude of the slope of thepressure profiles of the infusate channel and the filtrate channel arerelatively more steep (e.g., greater) than the magnitude of the slope ofthe pressure profile of the blood channel. As, illustrated the differentslopes cause a pre-dilution bias as there is a smaller pressuredifference between the blood and filtrate pressure profiles towards theinlet of the convective clearance device when compared to the outlet ofthe convective clearance device.

FIG. 5G illustrates a graph 590 of another example pressure profile ofeach of the channels in an example convective clearance device. Thepressures within the filtrate and infusate channels are controlledindependently of one another. This configuration can result in filtrateand infusate pressure profiles with different slopes. As illustrated,the example pressure profile of the infusate channel is steeper than theexample pressure profile of the filtrate channel. Controlling theinfusate and filtrate pressure profiles independently of one another canimprove the performance and reliability of the device. As illustrated,the infusate channel is operated in a pre-dilution configuration todecrease hematocrit within the device, and the filtrate channel isoperated in a post-dilution configuration to increase the soluteconcentration of the removed filtrate.

FIGS. 6A and 6B illustrate cross-sectional views of example microfluidicconvective clearance devices that includes elements to compensate forfluid volume changes in the channels along the length of the device.FIG. 6A illustrates a device 600 that includes a flow restrictingmaterial 601 within the infusate channel and filtrate channel, and FIG.6B illustrates a device 650 with a tapering channel design.

Referring to FIG. 6A, the device 600 includes an infusate channel 501, ablood channel 503, and a filtrate channel 502. The infusate channel 501and filtrate channel 502 are filled with a material 601 that isrestrictive to fluid flow and is an example pressure control feature.The material 601 can be a porous material, a mesh, a material consistingof sintered or packed particles, or an absorbent material. For example,the material 601 may include a plurality of packed particles, the volumeof the particles occupies space within the infusate channel. The volumeconsumed by the packed particles causes the channel to behave similar toa narrower channel. Effectively narrowing the channel results in anincreased pressure that counteracts the pressure drop that would beexperienced as the infusate passes from the infusate channel to theblood channel. In other terms, the packed particles cause the porosityof the channel to decrease, which increases the resistance (R) of thechannel.

Along the length of the channel, the flow (Q) through the channelchanges because fluid flows into or out of the channel through themembrane. For example, flow through the infusate channel decreases alongthe length of the infusate channel as fluid flows across the membranefrom the infusate channel to the blood channel. The pressure (P) in theinfusate channel is about equal to QR. The porosity of the material 601is controlled to give the proper R to affect the desired pressureprofile curve. In other implementations, the channels include mechanicalelements such as posts, ribs, struts, bumps, or other protrusions thatresult in resistance to flow. In some implementations, the material 601is located at specific regions of the infusate and filtrate channels. Insome implementations (as illustrated in FIG. 6A), the material 601 fillssubstantially the entire length of the infusate channel 501 and/orfiltrate channel 502, and the fluid resistivity of the material 601varies along the length of the channel to create a pressure gradientalong the length of the channels. For example, the material 601 in theinfusate channel 501 may include packed particles, the packing densityof which increase along the length of the channel causing the channel tobe more resistive along its length to flow. The increase in resistancealong the length of the channel compensates for the loss of fluidflowing from the infusate channel 501 and into the blood channel 503,for example. The material 601 within the filtrate channel 502 isconfigured to decrease in resistance along the length of the channel tocompensate for the increase in fluid volume received from the bloodchannel. In some implementations, when the material 601 runs the lengtha channel, the membrane can be glued or placed directly onto thematerial 601 with a low pressure epoxy. In some implementations, thedevice 600 can include any of the active pressure control featuresdescribed herein.

FIG. 6B illustrates device 650 that includes channels with differentcross-sectional areas. As illustrated, the height 651 (and/or width) ofthe infusate channel 501 and filtrate channel 502 change along thelength of the channels. The changing height, width, or cross-sectionalarea of the channel is another example pressure control feature. Theinfusate channel becomes shallower toward the end of the channel, whichresults in an increase in fluid pressure within the infusate channel. Insome implementations, the height and/or width of the channel may bechanged to affect the pressure within the channel. In someimplementations, the tapering of the channel height occurs along theentire length of the channel, as illustrated in FIG. 6B, and in otherimplementations, the tapering of the channel occurs only atpredetermined locations. For example, the last ⅓ of the infusate channelmay taper toward the infusate channel outlet. The filtrate channel 502also includes the pressure control feature of a tapering height. Thepressure control features of the infusate channel 501 and the filtratechannel 502 are complementary to one another in that as thecross-sectional area of the infusate channel 501 decreases, thecross-sectional area of the filtrate channel 502 increases to maintainparallel pressure profiles within the channels of the device 650.Smaller cross-sectional areas have higher resistance to flow compared tolarger cross-sectional areas, and the resistance to flow based oncross-sectional area can be calculated according to Hagan-Poiseuilleflow. Using the above described equation (P=QR) for the pressure alongthe length of each channel, the pressure (P) within each channel can becontrolled by adjusting the cross-sectional area to achieve the desiredR. In some implementations, the device 650 can include any of the activepressure control features described herein.

FIG. 6C illustrates device 660 that includes membranes 661 designed suchthat a property of the membrane changes along the length of thechannels. The membranes 661 are configured to enable different levels offluid transport at different positions along the length of the channels.Changing the property of the membrane is another example pressurecontrol feature. The membrane 661 between the infusate channel 501 andthe blood channel 503 is configured to decrease in porosity along itslength, making it more difficult for fluid to pass through the membrane661 towards the end of the infusate channel 501. The membrane 661between the blood channel 503 and the filtrate channel 502 complementsthe membrane 661 between the infusate channel 501 and the blood channel503. The membrane 661 between the blood channel 503 and the filtratechannel 502 increases in porosity along its length, making it easier forfluid to pass through the membrane 661 toads the end of the filtratechannel 502. Other properties of the membrane 661 that can be altered toaffect transmembrane pressure can include, but are not limited to, thecomposition of the membrane, the application of a sealant to portions ofthe membrane, the size of the finger-void area of the membrane, or anyother component in the membrane cross section which impacts flow acrossthe membrane surface. For example, a portion of the membrane may beheated to seal the pores of the membrane and prevent transport acrossthe membrane. In some implementations, the device 660 can include any ofthe active pressure control features described herein.

FIG. 6D illustrates a device 670 that includes channels configured tomaintain substantially linear pressure profiles along their respectivelengths. Each of the infusate channel 501, the filtrate channel 502, andthe blood flow channel 503 have a constant geometry along theirrespective lengths. To maintain the substantially linear pressureprofiles, the fluid flow through the infusate channel 501 and thefiltrate channel 502 is substantially greater than the the flow 514 fromthe infusate channel 501 to the blood channel 503 and the flow 515 fromthe blood channel 503 to the filtrate channel 502. In thisimplementation, the pressure drop in the infusate channel 501 and thefiltrate channel 502 remains substantially linear. In someimplementations, the flow through the infusate channel 501 and thefiltrate channel 502 is about 2 to about 8 or about 4 to about 6 timesgreater than the flow into or out of the infusate and filtrate channelsrespectively to channel 503. In some implementations, the device 670 caninclude any of the active pressure control features described herein.

In some implementations, the channels may include features to reduce theflexion of the membranes. The features can include discrete featuressuch as posts, chevrons, pyramids, hills, textured fields, or ribs; orcontinuous support mediums such as porous media, screens, through-holeetched thin films, secondary membranes, and sintered materials. Thedevice may include one or more of the support features or a combinationof discrete features and support mediums. In some implementations, themembrane support features prevent the membranes from deflecting under anapplied transmembrane pressure while also allowing filtrate to flowfreely through the membrane. Maintaining the position of the membranescan enable the blood channel to maintain its shape during the operationof the device—preserving shear rates in the blood channel.

FIG. 7 illustrates a cross-sectional view of a microfluidic convectiveclearance device 700 with membrane support features. The device 700includes posts 701 that maintain the height of the blood channel 503 bysecuring the membrane 703 to the ceiling of the infusate channel 501.The device 700 also includes a screen 702 that supports the membrane704, and prevents the membrane 704 form flexing into the filtratechannel 502 as fluid flows from the blood channel 503 to filtratechannel 502 through the membrane 704. For example, the screen 702 isless flexible or elastic than the membrane 704. In some implementations,the screen 702 does not affect convection through the membrane 704. Inother implementations, the screen 702 is configured to affect convectionthrough the membrane 704. For example, the screen 702 may be a supportstructure with holes milled through the structure. The density of theholes can be altered along the length of the screen 702 to control theamount of convection that occurs through the membrane 704 coupled to thescreen 702. In some implementations, the device 700 can include any ofthe active pressure control features described herein.

FIG. 8A illustrates a cross-sectional view along a length of amicrofluidic convective clearance device 800 with controlled infusionareas. The device 800 includes a infusate channel 501 separated from ablood channel 503 by a non-porous material 801. The non-porous materialincludes a plurality of openings 802, which may also be referred to asapertures. The openings 802 are another example pressure controlfeature. In some implementations, the device 800 can include any of theactive pressure control features described herein. A membrane 803separates the blood channel 503 form the filtrate channel 502.

The openings 802 are machined across a face of a non-porous material 801and provide fluidic communication between the infusate channel 501 andthe blood channel 503. In some implementations, the openings 802 arefabricated into the non-porous material 801 material by molding,machining, laser drilling, punching, or track etching. In someimplementations, the non-porous material 801 is a component of thesubstrate that defines one of the infusate channel 501 and the bloodchannel 503. For example, the non-porous material 801 may be the portionof the substrate defining the floor of the infusate channel 501. In someimplementations, the infusate channel 501 and the blood channel 503 aredefined on opposite sides of the same substrate, and the openings 802are holes machined between the infusate channel 501 and the bloodchannel 503.

The non-porous material 801 includes a plurality of openings 802. Theopenings 802 can be placed at discrete locations or distributed overportions of the blood channel. In some implementations, the openings 802have a pitch between about 1 cm and about 10 cm, about 4 cm and about 8cm, or about 4 cm and about 6 cm. The openings 802 are placed in thenon-porous material 801 above the blood channel at locations such thatthe infusion of liquid at the openings 802 can shape the hematocritprofile in the blood channel. In some implementations, the hematocritprofile is controlled by controlling the size and distribution of theopenings 802. The non-porous material 801 with the openings 802 provideboth the characteristics of a membrane as well as an access point forinfusion. The infusion flow distribution into the blood channel 503 canbe customized by changing the size, distribution, and length of eachopening 802 relative to another opening 802.

FIG. 8B illustrates a cross-sectional view across a width of themicrofluidic convective clearance device 800 with controlled infusionareas illustrated in FIG. 8A. The device 800 includes an infusatechannel 501 and a blood channel 503 separated by an opening 802. Afiltrate channel 502 is separated from the blood channel 503 by amembrane 803.

The infusate channel 501 of the device 800 is defined in a firstsubstrate layer 804, the blood channel 503 is defined in a secondsubstrate layer 806, and the filtrate channel 502 is defined in a thirdsubstrate layer 805. The channels are defined in their respectivesubstrates through photolithographic techniques, injection molding,direct micromachining, deep RIE etching, hot embossing, or anycombinations thereof. The substrate layers 804, 805, and 806 include athermoplastic such as, but not limited to, acrylic, polystyrene,polycarbonate, or any of the other materials described herein. Theopenings 802 are machined (e.g., laser drilled) into a wall of theinfusate channel 501. The openings 802 have a diameter between about 1μm and about 300 μm, between about 100 μm and about 250 μm, or betweenabout 150 μm and about 200 μm. In some implementations, each of thelayers of the device 800 are secured together with a bonding agent, suchas a glue or epoxy, and in other implementations, the layers are clampedtogether.

FIG. 8C illustrates a cross-sectional view across a width of anotherexample convective clearance device 810. The convective clearance device810 is similar to the convective clearance device 800, and includes afirst substrate 804, a second substrate 806, and a third substrate 805defining an infusate channel 804, a blood channel 805, and a filtratechannel 502, respectively. The convective clearance device 810 includestwo membranes 803. The first membrane 803 separates the infusate channel501 from the blood channel 503, and the second membrane 803 separatesthe blood channel 503 from the filtrate channel 502. The first membrane803 sits atop the second substrate 806 and the openings 802 definedtherein. In some implementations, the spacing of the openings 802 isselected to control the diffusion through the membrane 803. For example,the openings 802 can be more closely spaced toward the end of theinfusate channel 501 to enable greater transport through the membrane803. The effective membrane area of the first membrane 803 can beincreased with slots or pockets around the opening 802 in the non-porousmaterial 801 For example, the cross-sectional area of the openings 802can be increased to compensate for low pressure differences across themembrane 803 and enable more transport across the membrane 803. Thecross-sectional area of the openings 802 can be decreased to compensatefor high pressure differences across the membrane 803, which restrictsthe amount of convection across the membrane 803.

FIG. 9 illustrates a cross-sectional view of a microfluidic convectiveclearance device 900 with infusion zones. The different infusion zonesare another example pressure control feature. The device includes threeinfusion zones 902 a, 902 b, and 902 c (generally infusion zones 902)that are defined within an infusate channel. A distal end of each of therespective infusion zones 902 is defined by a intrachannel flow barrier906. The intrachannel flow barriers 906 are coupled to a permeablemembrane 907, and are specifically coupled to the permeable membrane 907at sealed, non-porous portions 908 of the membrane 907. The intrachannelflow barriers 906 are substantially non-porous and prevent flow from oneinfusion zone 902 to the next through the infusate channel or throughthe finger voids of the membrane 907. The fluid entering each of theinfusion zones 902 flows across the membrane 907 within the infusionzone 902 where the fluid was introduced to the device 900. The sealed,non-porous portions 908 of the membrane 907 can be formed by applyingheat or an epoxy to the membrane 907 to seal or clog the pores of themembrane as well the finger void within the membrane. In someimplementations, the portion of the membrane 907 within each of thedifferent infusion zones 902 is configured differently. For example, thefirst portion of the membrane 907 within the first infusion zone 902 amay have a higher porosity than compared to the portion of the membrane907 in the last infusion zone 902 c. In some implementations, theseparate infusion zones 902 generate stair-stepped pressure profilessimilar to those described in relation to FIG. 5D. In someimplementations, the above-described zones are formed in the filtratechannel to create independent filtrate zones.

Each of the infusion zones 902 include an inlet 905. The inlet 905supplies infusate to each of the respective infusate zones 902. Eachinlet 905 is coupled to a pump 909, which are each connected to acentral infusate reservoir 910. Each of pumps 909 are configured tooperate independently of one another, such that the flow rate andpressure to each inlet 905 (and infusion zone 902) is individuallycontrollable. For example, the pump 909 coupled to a last inlet 905 mayflow infusate into to the infusion zone 902 c at a lower pressure thancompared to a pump 909 coupled to the first infusion zone 902 a toaccount for a pressure decrease experienced toward the end of the bloodchannel.

FIG. 10 illustrates a cross-sectional view of a microfluidic convectiveclearance device 1000 with different infusion zones. As described abovein relation to FIG. 9, the device 1000 includes an infusate channel thatis divided into separate infusion zones 902 a-902 c. Each of theinfusion zones 902 are separated by an intrachannel flow barrier 906,which is coupled to a non-porous portion of the membrane 907. Eachinfusion zone 902 includes an inlet 905 that is supplied with infusatefrom a reservoir 910 vi a pump 909. Each infusion zone 902 also includesan outlet 911 so that a portion of the fluid introduced into theinfusion zone 902 passes through the membrane and a portion leavesthrough the outlet 911. The flow through the respective inlets 905 andoutlets 911 can be controlled by respective pumps 909 to more finelycontrol the pressures and infusion rate through the membrane 907 withineach infusion zone 902.

In some implementations, the sections of membrane 907 within each of theinfusion zones 902 are individual membrane portions 1001. In someimplementations, each of the membrane portions 1001 are separatepermeable membrane pieces coupled together to form a continuousmembrane. Each of the membrane portions 1001 along the length of thechannels can be configured differently. For example, each membraneportion 1001 can include a different porosity or be coated to change thepermeability of the portion. In some implementations, the shape anddensity of the finger-voids within the membrane portions 1001 arecontrolled to affect the transport across the membrane portions 1001.The finger-voids are the voids on the interior of the membrane portions1001. Larger finger-voids result in a less dense and less constrictivemembrane portion 1001, and smaller finger-voids result in a denser andmore restrictive membrane portion 1001.

In some other implementations, membrane portions 1001 are created bycrimping, molding, or potting a permeable membrane to create individualchambers. In some implementations, molding is inserted around themembrane portions 1001 to prevent flow between membrane portions 1001.In some implementations, the crimp is created by forcing or potting themembrane onto a molded plate. Similarly, gluing, welding, or applying asolvent can be used to define membrane portions 1001 and prevent thelateral flow within the membranes. The glue bond or weld that forms eachend of a portion 1001 is designed to prevent lateral flow betweenadjacent membrane portions 1001, while at the same time not disturbingthe surface of the membrane portion 1001 facing the blood channel.

In some implementations, the transverse membrane pressure can also becontrolled in any of the devices described herein by controlling theproperties of the interchannel flow barriers along the length of thedevice. For example, the interchannel flow barrier separating theinfusate channel and the blood channel may become more porous along thelength of the channels to compensate for the decrease in pressure in theinfusate channel as it loses volume to the blood flow channel. Thechange in porosity of the interchannel flow barrier can be controlled bycontrolling the thickness of the interchannel flow barrier along thelength of the channel. For example, membranes can be stacked so that atthe distal end, the membrane stack separating the infusate channel orfiltrate channel from the blood channel includes only a single layer ofmembrane. Upstream, towards the proximal side of the device, additionallayers of membrane are added to the membrane stack between the bloodchannel and the filtrate channel to add additional restriction to thevertical flow path. As the resistance of each membrane has an additivecomponent in the stack, the pressures between the membranes is set sothat no one membrane sees excessive transverse pressure. This has aneffect of insuring that each individual membrane sees only the targetpressure range in which it can function effectively. In anotherimplementation, the pore size of the membranes can be varied along thelength of the interchannel flow barrier to control the pressure drop.Epoxy or heat can be applied to the membrane at specific portions tocontrol the restrictiveness of the interchannel flow barrier. Applyingheat to a surface of the interchannel flow barrier can melt and seal thepores in the interchannel flow barrier. The amount of heat (or epoxy)can be controlled to regulate the percentage of pores that are sealedduring the sealing process.

In some implementations, the properties of the membrane itself can bechanged, so that portions of the membrane function effectively at higherpressure and some at lower pressure. Aligning properly to the channelyields an effective means to insure that membrane is behaving asdesired.

FIG. 11 illustrates a flow chart of an example method 1100 for cleansinga fluid. The method 1100 includes introducing a first fluid into aninfusate channel (step 1102). The method 1100 also includes introducingblood into a blood flow channel (step 1104). At least a portion of thefirst fluid is flowed through a pressure control feature (step 1106).The pressure control feature substantially parallelizes a pressureprofile of the infusate channel and a pressure profile of the blood flowchannel. That is, the pressure control feature renders the inter-channelpressure differential to be substantially constant along substantiallythe entire length of the channels. The method 1100 also includescollecting a second fluid from an outlet of a filtrate channel (step1108).

As set forth above, the method 1100 includes introducing a first fluidinto an infusate channel (step 1102). The infusate channel can be aninfusate channel of any of the devices described herein, and the firstfluid can be infusate. The method 1100 also includes introducing bloodinto a blood flow channel (step 1104). In some implementations, theblood and the infusate channels are parallel and complementary to oneanother. For example, the blood and the infusate channels overlap oneanother and are separated by a membrane or other interchannel flowbarrier. In some implementations, the blood and the infusate are flowedthrough the device in the same direction. In some implementations, theinfusate is introduced into the infusate channel at a relatively higherpressure than the blood is introduced to the blood flow channel.

The method 1100 also includes flowing a portion of the first fluidthrough a pressure control feature (step 1106). As described above, thepressure control feature can be a feature of the infusate channel and/orthe interchannel flow barrier separating the infusate channel and bloodchannel. For example, the pressure control feature can be a tapering ofthe cross-sectional area of the infusate channel or a plurality ofapertures defined in the interchannel flow barrier. In someimplementations, the portion of the first fluid is driven through theinterchannel flow barrier or the pressure control feature by thepressure gradient between the infusate channel and the blood channel. Insome implementations, the blood channel and/or the filtrate channel alsoinclude a pressure control feature that substantially parallelizes thepressure profile of the blood channel with a pressure profile of thefiltrate channel.

The method 1100 also includes collecting a second fluid from an outletof a filtrate channel (step 1108). In some implementations, the secondfluid is a filtrate that is flowed through a filtrate channel of thedevice. The filtrate channel can be complementary to the blood flowchannel and be separated from the blood flow channel by a secondinterchannel flow barrier. The second fluid can be introduced to thedevice a pressure relatively lower than the pressure the blood isintroduced to the device. The pressure differentials between theinfusate channel, blood channel, and filtrate channel drives a portionof the infusate into the blood and then a portion of the blood into thefiltrate channel—cleansing the blood. The portion of the blood driveninto the filtrate channel can be plasma, urea, or other waste particles,and are generally referred to as particles. As the fluids flow throughthe device, the particles are driven into the filtrate channel. Thefiltrate (now including the particles) is collected as the filtrateexits the device.

FIG. 12 illustrates a graph 1200 comparing transmembrane pressure to theflux across the filtrate membrane. The graph 1200 illustrates that asthe transmembrane pressure increases, the increase in flux is initiallylinear, as indicated by line 1202. At higher relative transmembranepressures, the flux is non-linear, and in some cases can begin todecline. The decrease in the flux's slope as the transmembrane pressureincreases can be attributed to the formation of a protein layer at thesurface of the filtrate membrane. Increasing the transmembrane pressurepast a “critical flux” point 1204 (also referred to as a criticaltransmembrane pressure 1204) can cause damage to the membrane'sfiltration capacity. As illustrated in FIG. 12, the critical flux point1204 is at about 250 mmHg. The shaded region 1206 indicatestransmembrane pressures past the critical flux point 1204 that may causedamage to the membrane. Increasing the flux past the critical flux point1204 can result in permanent damage to the membrane's filtrationcapacity as the protein layer is compressed against the filtratemembrane and increases hydraulic resistance across the membrane. Thehydraulic resistance increases because the proteins in the blood filland clog the pores of the membrane or a strong gel layer forms on thesurface of the membrane. In some implementations, the damage isirreversible. The location of the critical flux point 1204 along theflux curve (and the shape of the flux curve itself) is dependent on manyfactors, such as the shear rate of the fluid flowing through thechannels, protein concentrations within the fluid, membrane properties,and channel size. Accordingly, FIG. 12 represents one example criticalflux point 1204, and in other implementations, the critical flux point1204 can occur at pressure greater than or less than that illustrated inFIG. 12. In some implementations, the critical flux point 1204 can bethe point where the slope of the flux is about 50% less than the initiallinear slope of the flux. In some implementations, the critical fluxpoint 1204 is determined experimentally. For example, for a givensystem, the pressures can be cycled between a baseline and an elevatedpressure. With each cycle the elevated pressure is increased withrespect to the elevated pressure used in the previous cycle. The cyclingprocess can be continued until a permanent reduction of flux isexperienced upon returning to the baseline pressure. In anotherexperimental example, the flux across the membrane is increased indiscrete steps until the transmembrane pressure begins to rise withoutan accompanying increase in flux.

In some implementations, transmembrane pressure profiles between theblood channel and the filtrate channel can violate a criticaltransmembrane pressure, which can result in the device not functioningoptimally. The pressure control features described herein can provideprotection against violating a known critical transmembrane pressure.Controlling the pressure to not violate the known critical transmembranepressure can improve membrane reliability and device durability. Forexample, one or more of the pressure control devices described hereincan be used to limit the amount of pre-dilution bias or post-dilutionbias. Limiting the pre- and post-dilution bias can enable the operationof the device without violating the critical transmembrane pressurealong the length of the device. In some implementations, notsubstantially violating the critical transmembrane pressure improves thedevice's long-term durability. Improving the durability of the membranecan increase total filtrate production over the course of a treatmentbecause the resistance across the membrane remains relatively low. Incontrast, violating the critical transmembrane pressure can providehigher short-term filtrate flow, but can ultimately result in lowertotal filtrate production over the course of a treatment as themembrane's resistance increases during the treatment. In someimplementations, the highest filtrate production is achieved in a devicethat is operating with parallel pressure profiles for the blood andfiltrate channels with the average transmembrane pressure at or lessthan the critical transmembrane pressure. Operating the device in thiscase, can result in lower membrane and filter costs, and also lessforeign body interaction between the blood and the filter components.

FIG. 13 illustrates a cross-sectional view of a microfluidic convectiveclearance device 1300 for use in hemofiltration. The device 1300 is atwo-layer device that includes a blood flow channel 503 and a filtratechannel 502. In contrast to the device 500 describe above in relation toFIG. 5A, the device 1300 does not include a infusate channel 501. Thedevice 1300 is configured to include any of the pressure controlfeatures described herein to maintain a predetermined pressure profilein the blood channel 503 and the filtrate channel 502. As describedabove in relation to device 500, the blood channel 503 is separated fromthe filtrate channel 502 by a membrane 504. The filtrate channel 502 isin fluid communication with a filtrate reservoir 506 via manifolds suchas those described above in relation to FIG. 1A. A pump 509 is placedin-line with the filtrate reservoir 506. A valve 510 is placed in-linewith the pump 509. In some implementations, passive and/or activepressure control features other than a valve 510 are placed in-line withthe filtrate channel 502. For example, the pressure profile of thefiltrate channel 502 can be controlled with a variable flow pump or adiaphragm chamber.

In some implementations, the control system of the device 1300 controlsthe operational state of the valve 510 to control the pressure profileof the filtrate channel 502. In some implementations, the control systemcontrols the valve 510 (or other controllable flow control device) suchthat the difference between the filtrate channel's pressure profile andthe blood channel's pressure profile is below a predetermined pressure.For example, the control system can control valve 510 to prevent thepressure difference between the blood channel's pressure profile and thefiltrate channel's pressure profile from exceeding a criticaltransmembrane pressure. In one example, the control system may increasethe inlet pressure of the filtrate channel to drive the pressure profileof the filtrate toward the pressure profile of the blood channel. As thepressure profile of the filtrate channel raises toward the pressureprofile of the blood channel, the pressure difference reduces to staybelow the critical transmembrane pressure. In another example, thecontrol system may control the influx and outflow pumps to control therate at which new filtrate is introduced and used filtrate is removedfrom the device 1300. The control system can also control other activepressure control systems, such as a variable flow pump and a diaphragmchamber.

FIG. 14 illustrates a flow chart of an example method 1400 for cleansinga fluid. The method 1400 includes introducing a first fluid into aninfusate channel (step 1402). The method 1100 also includes introducingblood into a blood flow channel (step 1404) and a filtrate into afiltrate channel (step 1406). A pressure control feature is used to seta first slope of the filtrate's pressure profile (step 1408). Thepressure control feature is then used to set a second slope of thefiltrate's pressure profile (step 1410).

As set forth above, the method 1400 includes introducing a first fluidinto an infusate channel (step 1402). The infusate channel can be aninfusate channel of any of the devices described herein, and the firstfluid can be infusate. The method 1400 also includes introducing bloodinto a blood flow channel (step 1404). In some implementations, theblood and the infusate channels are parallel and complementary to oneanother. For example, the blood and the infusate channels overlap oneanother and are separated by a membrane or other interchannel flowbarrier. In some implementations, the blood and the infusate are flowedthrough the device in the same direction. In some implementations, theinfusate is introduced into the infusate channel at a relatively higherpressure than the blood is introduced to the blood flow channel.

The method 1400 also includes introducing a second fluid into thefiltrate channel (step 1406). In some implementations, the second fluidis a filtrate. The filtrate channel can be any of the filtrate channelsdescribed herein. The filtrate can be flowed through the device in thesame direction as the blood and insulate. In some implementations, thefiltrate and the infusate are flowed in the opposite direction throughthe device with respect to the direction of the blood flow. In someimplementations, the second fluid is a dialysate.

Each of the filtrate channel, blood channel, and infusate channel has apressure profile along its length. The method 1400 also includes settinga first slope of the filtrate channel's pressure profile (step 1408).The slope of the pressure profile can be set with any of thecontrollable flow control devices described herein. For example, adesired pressure profile can be supplied to the system controller, whichcan control a pressure valve near the inlet of the filtrate channel tocontrol the pressure of the filtrate entering the filtrate channel.

The method 1400 also includes setting a second slope of the filtratechannel's pressure profile (step 1410). The slope of the pressureprofile can be set with any of the controllable flow control devicesdescribed herein. In some implementations, the first and the secondslopes of the filtrate channel are set with respect to slope of theinfusate channel's pressure profile or the blood channel's pressureprofile. For example, the slope of the filtrate channel's pressureprofile may initially be set to be less than the slope of the bloodchannel's pressure profile and then be set to be greater than the slopeof the blood channel's pressure profile. In another implementation, theslope of the filtrate channel's pressure profile may initially be set tobe greater than the slope of the blood channel's pressure profile andthen be set to be less than the slope of the blood channel's pressureprofile. In some implementations, the method 1400 also includescontrolling the slope of the pressure profile of the infusate and bloodchannels.

The slope of each of the pressure profiles is controlled by the controlsystem. The control system is configured to control each of theconvective clearance device's controllable flow control devices. Thecontrollable flow control devices can include any of a recirculatingpump, a proportional valve, a diaphragm chamber, an influx pump, and anoutflow pump. The control system controls the operational state of thecontrollable flow control device. For example, the control system maycontrol a regulator coupled to a diaphragm chamber. By controlling theopening of the regulator, the control system can cause the introductionof pressure into the diaphragm chamber, which constricts the passagewaythrough the diaphragm chamber and increases the pressure of the fluidexiting the diaphragm chamber. In some implementations, one or more ofthe channels in the convective clearance device includes a plurality ofcontrollable flow control devices. For example, the infusate andfiltrate channels can include a controllable flow control devicepositioned toward the inlet and the outlet of each channel.

In some implementations, the control system receives pressuremeasurements from pressure sensors placed along the length of any of thefiltrate, blood, and infusate channels. For example, each of thechannels can include a plurality of pressure sensors distributed alongthe length of each of the channels. In some implementations, thepressure sensors are placed toward the inlet and outlet of any of thefiltrate, blood, and infusate channels. The control system uses thepressure measurements from the pressure sensors to form a feedback loopto maintain the set slopes of each of the pressure profiles.

In some implementations, the control system maintains a predeterminedpressure difference between the pressure profile of the filtrate channeland the pressure profile of the blood channel. The control system canreceive pressure measurement from the pressure sensors placed along thelength of the blood and filtrate channels to ensure that the pressuredifference remains below a critical transmembrane pressure along thelength of the device.

The disclosed system and methods may be embodied in other specific formswithout departing from the spirit or essential characteristics thereof.The forgoing implementations are therefore to be considered in allrespects illustrative, rather than limiting of the invention.

As utilized herein, the terms “substantially” and similar terms areintended to have a broad meaning in harmony with the common and acceptedusage by those of ordinary skill in the art to which the subject matterof this disclosure pertains. It should be understood by those of skillin the art who review this disclosure that these terms are intended toallow a description of certain features described without restrictingthe scope of these features to the precise numerical ranges provided.Accordingly, these terms should be interpreted as indicating thatinsubstantial or inconsequential modifications or alterations of thesubject matter described and are considered to be within the scope ofthe disclosure.

What is claimed:
 1. A microfluidic device comprising: a first layerdefining an infusate channel, the infusate channel having a firstpressure profile with a first slope along a length of the infusatechannel; a second layer defining a blood channel in fluidiccommunication with the infusate channel, the blood channel having asecond pressure profile with a second slope along a length of the bloodchannel; a filtrate layer defining a filtrate channel in fluidiccommunication with the blood channel, the filtrate channel having athird pressure profile with a third slope along a length of the filtratechannel; a first interchannel flow barrier separating the infusatechannel and the blood channel, wherein the first interchannel flowbarrier includes a plurality of openings defined through the firstinterchannel flow barrier, allowing passage of fluid from the infusatechannel into the blood channel; a second interchannel flow barrierseparating the filtrate channel and the blood channel; a firstcontrollable flow control device along a length of the filtrate channelconfigured to actively control the third slope of the third pressureprofile along the length of the filtrate channel relative to the secondslope of the second pressure profile along the length of the bloodchannel; a second controllable flow control device configured toactively control the first slope of the first pressure profile along thelength of the infusate channel relative to the second slope of thesecond pressure profile along the length of the blood channel; and acontrol system configured to modify a state of the first controllableflow control device and the second controllable flow control device suchthat the first slope of the first pressure profile along the length ofthe infusate channel is substantially parallel to the third slope of thethird pressure profile along the length of the filtrate channel.
 2. Themicrofluidic device of claim 1, further comprising at least one pressuresensor coupled to the control system, wherein the control system isconfigured to modify the state of the first or second controllable flowcontrol device responsive to an output of the at least one pressuresensor.
 3. The microfluidic device of claim 1, wherein the first andsecond controllable flow control devices are one of a recirculatingpump, a proportional valve, a diaphragm chamber, or an outflow pump. 4.The microfluidic device of claim 1, wherein the control system isconfigured to control the first and second controllable flow controldevices such that the first pressure profile is substantially parallelto the second pressure profile.
 5. The microfluidic device of claim 1,wherein the control system is configured to cause the first controllableflow control device to achieve a state such that the slope of the thirdpressure profile is greater than the slope of the second pressureprofile.
 6. The microfluidic device of claim 1, wherein the controlsystem is configured to cause the first controllable flow control deviceto achieve a state such that the slope of the third pressure profile isless than the slope of the second pressure profile.
 7. The microfluidicdevice of claim 1, comprising a third controllable flow control deviceconfigured to, along with the first controllable flow control device,actively control the slope of the third pressure profile along thelength of the filtrate channel relative to the slope of the secondpressure profile along the length of the blood channel.
 8. Themicrofluidic device of claim 1, wherein the blood channel has a heightin the range of about 50 μm to about 500 μm, a width in the range ofabout 50 μm to about 900 μm, and a length in the range of about 3 cm toabout 30 cm.
 9. The microfluidic device of claim 1, wherein the secondinterchannel flow barrier comprises a membrane.
 10. The microfluidicdevice of claim 1, wherein the second interchannel flow barrier is asterility barrier.
 11. The microfluidic device of claim 1, wherein thefirst interchannel flow barrier further comprises a membrane locatedbetween the infusate channel and the blood channel.
 12. The microfluidicdevice of claim 1, wherein the second layer defines a plurality of bloodchannels.
 13. The microfluidic device of claim 12, wherein the pluralityof blood channels are in fluid communication with the infusate channelthrough the plurality of openings in the first interchannel flowbarrier.
 14. The microfluidic device of claim 13, wherein the pluralityof openings through the first interchannel flow barrier are positionedsequentially along the length of the infusate channel, and each of theopenings spans across all of the blood channels in the second layer. 15.The microfluidic device of claim 14, wherein the openings through thefirst interchannel flow barrier have a pitch along the length of theinfusate channel of between about 1 cm and 10 cm.
 16. The microfluidicdevice of claim 14, wherein the spacing of the openings through thefirst interchannel flow barrier decreases along the length of theinfusate channel.
 17. The microfluidic device of claim 14, wherein thesize of the openings through the first interchannel flow barrierincreases along the length of the infusate channel.
 18. The microfluidicdevice of claim 1, wherein the first interchannel flow barrier comprisesa substantially non-porous material through which the openings aredefined.
 19. The microfluidic device of claim 18, wherein the firstinterchannel flow barrier includes a portion of the first layer defininga floor of the infusate channel.